Medical abortion: what does the research tell us?

Dr. Ellen R. Wiebe''s study of the use of methotrexate and misoprostol in combination for early termination of intrauterine pregnancy (see pages 165 to 170 of this issue) is the first Canadian study of the use of this drug combination for medical abortion. The authors compare Wiebe''s findings with those of earlier studies on methotrexate and misoprostol, as well as with European findings on the use of mifepristone with prostaglandins. The authors argue that although the methotrexate-misoprostol combination appears to be reasonably safe for the woman, the failure rate and the teratogenicity of methotrexate and misoprosol give cause for concern. The authors conclude that medical abortions ought to be offered only where there is adequate access to laboratory and surgical facilities and where losses to follow-up are systematically minimized to reduce the potential for continued pregnancy resulting in congenital abnormality.     

Teratogen update: methotrexate

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.     

Failed medical management in ovarian pregnancy despite favorable prognostic factors--a case report

Primary ovarian pregnancy is a rare form of ectopic pregnancy that must be demonstrated with use of 4 Spiegelberg criteria. It is usually diagnosed at laparotomy or laparoscopy, although it may resemble a hemorrhagic corpus luteum. Successful conservative management of ovarian pregnancy with methotrexate has been reported only occasionally. This may be partly because of the rarity of this condition and partly because when medical treatment is successful, the patient does not need to undergo laparotomy or laparoscopy, and an occasional ovarian pregnancy may have been diagnosed as a tubal pregnancy. We present a case of ovarian pregnancy (diagnosed at laparotomy) for which initial medical management with methotrexate failed despite favorable prognostic factors. Whether the unusual location (ovary) could have contributed toward treatment failure is unknown.     

Abortion induced with methotrexate and misoprostol.

OBJECTIVE: To determine the outcome and side effects of a new drug protocol to induce abortion. DESIGN: Case series. SETTING: An urban primary care practice. PATIENTS: One hundred consecutive patients who requested elective termination of pregnancies of less than 8 weeks'' gestation. INTERVENTION: Subjects received methotrexate (50 mg/m2 body surface area, administered intramuscularly) and, 3 days afterward, misoprostol (800 micrograms, given vaginally). OUTCOME MEASURES: Number of abortions induced within 24 hours and within 10 days of misoprostol administration, number of surgical aspirations conducted because of incomplete abortion, mean amount of bleeding and pain and the number of women who, if faced with the same situation, said they would again choose a drug-induced abortion over a surgical one. RESULTS: Abortion occurred within 24 hours of misoprostol administration among 48 women and within 10 days among 69 women. In total, 89 women had an abortion without surgical aspiration. Of these women, 71 said they would choose a drug-induced abortion if faced with the choice again. CONCLUSION: Abortion induced with methotrexate and misoprostol appears to be a feasible alternative to surgical abortion and deserves further study.     

A case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype

BACKGROUND: Methotrexate (MTX) embryopathy was described nearly 50 years ago, when this agent began to be used as a cancer treatment and abortifacient. In this report we describe a case with typical features of MTX syndrome together with new features to expand the phenotype. CASE: A 29-year-old woman decided to terminate her unwanted pregnancy because of ill health, as she had conceived soon after her last delivery by cesarian section. At 6 weeks of gestation, she took 2.5 mg of MTX 3 times a day for 7 days. The pregnancy termination failed, and the pregnancy was carried to term. A female infant was delivered who was growth retarded and had characteristic features of MTX embryopathy in addition to holoprosencephaly and other brain malformations, facial hypertrichosis, and long eyelashes-features that have not hitherto been described. CONCLUSIONS: We report the first case of holoprosencephaly in association with MTX exposure during the first 6 weeks of gestation. Physicians and the public should be aware of the effects of MTX on the fetus during pregnancy.     

Methotrexate therapy. Nonsurgical management of ectopic pregnancy.

Ectopic pregnancy has become a surgical epidemic over the past two decades. To minimize the morbidity, mortality, and financial burden created by this rapidly growing health problem, nonsurgical alternatives have been investigated, including treatment with methotrexate. We reviewed current literature to evaluate the safety, efficacy, and costs associated with methotrexate treatment of tubal pregnancy. To date, 17 studies have reported on 400 patients with tubal pregnancies treated with parenteral methotrexate; the overall success rate was 92% (95% confidence interval, 89% to 95%). Single-dose parenteral methotrexate has been shown to be safe, effective, and associated with minimal costs when used in carefully selected patients. A prospective, randomized clinical trial comparing medical and surgical management of ectopic pregnancy is needed to assess the risks, benefits, and costs of these two approaches.     

超声引导下局部注射甲氨蝶呤治疗异位妊娠的临床应用

目的:探讨超声引导下局部注射甲氨蝶呤(MTX)治疗异位妊娠的疗效。方法:对30例异位妊娠患者在超声引导下行MTX病灶局部注射,术后给予米非司酮口服(25mg,2次/天,共3天)。治疗前及治疗后每周一次抽血查β-hCG直至其降至正常范围内。结果:30例患者中,29例(96.7%)通过治疗后β-hCG降至正常,1例(3.3%)治疗失败后行外科手术。结论:超声引导下MTX局部注射治疗异位妊娠技术操作简单,疗效肯定,对适应范围内的病人是值得考虑的治疗方法。     

Reproductive Outcomes Following Ectopic Pregnancy: Register-Based Retrospective Cohort Study

Background

We aimed to compare reproductive outcomes following ectopic pregnancy (EP) versus livebirth, miscarriage, or termination in a first pregnancy.

Methods And Findings

A retrospective cohort study design was used. Scottish national data on all women whose first pregnancy occurred between 1981 and 2000 were linked to records of a subsequent pregnancy. The exposed cohort comprised women with an EP in their first pregnancy. There were three unexposed cohorts: women with livebirth, miscarriage, and termination of their first pregnancies. Any differences in rates of second pregnancy, livebirth, EP, miscarriage, or terminations and complications of a second ongoing pregnancy and delivery were assessed among the different exposure groups. A total of 2,969 women had an initial EP; 667,299 had a livebirth, 39,705 women miscarried, and 78,697 terminated their first pregnancies. Women with an initial EP had an increased chance of another pregnancy within 2 years (adjusted hazard ratio (AHR) 2.76 [95% CI 2.58–2.95]) or after 6 years (AHR 1.57 [95% CI 1.29–1.91]) compared to women with a livebirth. In comparison with women with an initial miscarriage, women who had an EP had a lower chance of a second pregnancy (AHR 0.53 [95% CI 0.50–0.56]). Compared to women with an initial termination, women with an EP had an increased chance of a second pregnancy (AHR 2.38 [95% CI 2.23–2.55]) within 2 years. Women with an initial EP suffered an increased risk of another EP compared to women with a livebirth (AHR 13.0 [95% CI 11.63–16.86]), miscarriage (AHR 6.07 [95% CI 4.83–7.62]), or termination (AHR 12.84 [95% CI 10.07–16.37]). Perinatal complications in a pregnancy following EP were not significantly higher than those in primigravidae or in women with a previous miscarriage or termination.

Conclusion

Women with an initial EP have a lower chance of conception than those who miscarry but an increased risk of a repeat EP in comparison with all three comparison groups. A major limitation of this study was the inability to separate women using contraception from those who were intending to conceive. Please see later in the article for the Editors'' Summary     

Decidual lymphocytes of human spontaneous abortions induce apoptosis but not necrosis in JEG-3 extravillous trophoblast cells

The human decidua contains an unusually high proportion of lymphocytes, mainly NK and T cells, which are potentially cytotoxic to the trophoblast when they are stimulated with certain cytokines. Given the high incidence of spontaneous abortion in humans and other species, our working hypothesis is that decidual lymphocytes are involved in immunological mechanisms that attack the trophoblast and induce abortion when any gestational problem arises. To test this hypothesis, flow cytometry was used to compare decidual lymphocyte populations in first-trimester spontaneous abortions and elective terminations of first-trimester pregnancy. We found significantly higher proportions of decidual lymphocytes that expressed activation markers, and of T cells (mainly T helper cells) in spontaneous abortions than in elective terminations of pregnancy. Decidual lymphocytes from spontaneous abortion, like decidual lymphocytes from elective termination of pregnancy and peripheral blood lymphocytes, were however, unable to lyse the JEG-3 extravillous cytotrophoblast cell line in a (51)Cr-release assay. Nevertheless, decidual lymphocytes from spontaneous abortion, unlike decidual lymphocytes from elective termination of pregnancy and peripheral blood lymphocytes, induced apoptosis in JEG-3 cells as determined by DNA fragment-release assay. Hematoxylin and eosin staining showed a significantly higher proportion of apoptotic JEG-3 cells when these cells were treated with decidual lymphocytes from spontaneous abortion than when JEG-3 cells were cultured with decidual lymphocytes from elective termination of pregnancy. The ultrastructural signs of apoptosis were confirmed by electron microscopy. These data support the hypothesis that activated decidual lymphocytes participate in human spontaneous abortion by inducing apoptosis but not necrosis of the trophoblast.     

Prenatal diagnosis, pregnancy terminations and prevalence of Down syndrome in Atlanta

BACKGROUND: The impact of prenatal diagnosis on the live birth prevalence of Down syndrome (trisomy 21) has been described. This study examines the prevalence of Down syndrome before (1990-1993) and after inclusion of prenatally diagnosed cases (1994-1999) in a population-based registry of birth defects in metropolitan Atlanta. METHODS: We identified infants and spontaneous fetal deaths with Down syndrome (n = 387), and pregnancies electively terminated after a prenatal diagnosis of Down syndrome (n = 139) from 1990 to 1999 among residents of metropolitan Atlanta from a population-based registry of birth defects, the Metropolitan Atlanta Congenital Defects Program (MACDP). Only diagnoses of full trisomy 21 were included. Denominator information on live births was derived from State of Georgia birth certificate data. We compared the prevalence of Down syndrome by calendar period (1990-1993, 1994-1999), maternal age (<35 years, 35+ years), and race/ethnicity (White, Black, other), using chi-square and Fisher's exact tests. RESULTS: During the period when case ascertainment was based only on hospitals (1990-1993), the prevalence of Down syndrome was 8.4 per 10,000 live births when pregnancy terminations were excluded and 8.8 per 10,000 when terminations were included. When case ascertainment also included perinatal offices (1994-1999), the prevalence of Down syndrome was 10.1 per 10,000 when terminations were excluded and 15.3 when terminations were included. During 1990-1993, the prevalence of Down syndrome was 24.7 per 10,000 among offspring to women 35+ years of age compared to 6.8 per 10,000 among offspring to women <35 years of age (rate ratio [RR] = 3.65, 95% confidence interval [CI] = 2.53-5.28). During 1994-1999, the prevalence of Down syndrome was 55.3 per 10,000 among offspring to women 35+ years compared to 8.5 per 10,000 among offspring to women <35 years (RR = 6.55, 95% CI = 5.36-7.99). There was no statistically significant variation in the prevalence of Down syndrome by race/ethnicity within maternal age and period of birth strata. During 1994-1999, the proportion of cases that were electively terminated was greater for women 35+ years compared to women <35 years (RR = 5.10, 95% CI = 3.14-8.28), and lower for Blacks compared to Whites among women 35+ years of age (RR = 0.33, 95% CI = 0.16-0.66). CONCLUSIONS: In recent years, perinatal offices have become an important source of cases of Down syndrome for MACDP, contributing at least 34% of cases among pregnancies in women 35+ years of age. Variation in the prevalence of Down syndrome by race/ethnicity, before or after inclusion of cases ascertained from perinatal offices, was not statistically significant. Among Down syndrome pregnancies in mothers 35+ years we found a lower proportion of elective termination among Black women compared to White women. We suggest that future reports on the prevalence of Down syndrome by race/ethnicity take into account possible variations in the frequency of prenatal diagnosis or elective termination by race/ethnicity.     

Prenatal diagnosis of trisomy 12 mosaicism: normal development of a 3 years old female child

Trisomy 12 mosaicism is a rare chromosomal mosaicism in prenatal diagnosis by amniocentesis. In the literature we found at least 27 cases. 13 Pregnancies were terminated, with multiple congenital anomalies (MCA) in 2 out of 13. Of the 12 liveborns with follow-up ranging from 0 to 5 years, 5 presented MCA and died within the first weeks. 2 Fetus died during pregnancy and further data are lacking. A normal outcome, with limited follow up however, was reported in 7/12 liveborns without congenital anomalies and is well demonstrated in the presently reported girl. We describe the 3-years follow up in a girl with trisomy 12 mosaicism, detected by amniocentesis for advanced maternal age. She is a healthy girl with normal physical and psychomotor development.     

Pregnancy termination

During pregnancy, the antiprogestin mifepristone will induce uterine contractions, increase the sensitivity of the myometrium to prostaglandin, and ripen the cervix. These effects indicate that mifepristone can be used for termination of pregnancy. The clinical experience has shown that mifepristone is sufficiently effective for this purpose only if combined with a suitable prostaglandin, e.g. gemeprost or misoprostol. The combined treatment has been used for termination of early pregnancy (up to 63 days of amenorrhea) and for termination of second trimester pregnancy. During early pregnancy, the recommended dose of mifepristone is 600 mg (although 200 mg seems sufficient), followed 36-48 h later by 0.4-0.8 mg misoprostol administered either orally or vaginally, or vaginal administration of 1.0 mg gemeprost. For termination of second trimester pregnancy, the treatment with mifepristone is most commonly combined with 1.0 mg gemeprost repeated at 3-6-h intervals. The combined treatment is as effective and safe during early pregnancy as is the alternative vacuum aspiration and is also equally acceptable if the woman is allowed to choose the method she prefers. During the second trimester, the pretreatment will significantly reduce the duration of labor, dose of prostaglandin, and the frequency of side effects.     

Value of routine ultrasound scanning at 19 weeks: a four year study of 8849 deliveries.

OBJECTIVE--To evaluate the effectiveness of routine ultrasound scanning at 19 weeks'' gestation in an unselected population in terms of accuracy of detection of fetal structural abnormality and the effect on obstetric and neonatal care. DESIGN--Prospective study over four years. Scans performed by radiographers with overall supervision by a radiologist. SETTING--Ultrasound department of district general hospital. SUBJECTS--All pregnant women were offered scans; 8523 of 8849 (96%) accepted. MAIN OUTCOME MEASURES--Information obtained from hospital records, genetic analysis, and post-mortem findings. RESULTS--166 fetal anomalies occurred; 140 were detected at 19 weeks (sensitivity 85%; specificity 99.9%). In 27 cases fetuses were shown to have severely crippling or lethal abnormalities; termination of pregnancy was requested in 25. Early diagnosis influenced timing and place of delivery in babies with severe cardiac or gastrointestinal anomalies. CONCLUSION--Scanning at 19 weeks with availability of termination can reduce perinatal morbidity and mortality. Scanning can be performed in a general ultrasound department with adequate counselling facilities and close cooperation between radiographers, midwives, obstetricians, paediatricians, and the radiologist.     

Cranial computertomography in children with acute lymphatic leukemia (ALL) and non Hodgkin-lymphoma (NHL) after different methods of CNS-treatment

42 children with acute lymphatic leukemia (ALL) or non-Hodgkin lymphoma (NHL) were subjected to cranial computer tomography (CT). 4 groups were formed according to CNS therapy. Group 1: 18 children in complete first remission after CNS prophylaxis with intrathecal 198 Au-colloid and methotrexate were examined between 3 1/2 and 7 1/3 years after beginning of therapy. 15 patients had normal computer tomograms, only 3 children had slight anomalies. The quantitative assessment of the computer tomograms yielded normal results for all 18 children. Group 2: 8 children were examined before CNS prophylaxis. 1 child had a connatal septum pellucidum cyst, 4 children had no anomalies and 3 children slight anomalies. The deviations from normal in groups 1 and 2 should be physiological variations. Group 3: 6 children were examined between 10 months and 8 1/4 years after termination of prophylactic CNS-irradiation (18-22.5 Gy) in combination with intrathecal methotrexate. Normal findings were obtained for 2 patients only. The other children had distinct cortical, subcortical or cerebellar atrophies and calcification of stem ganglia. Neurological complications had temporarily appeared in one child after skull irradiation. Group 4: A CT was made of 10 children during or after meningosis leukemia. The children who had received 198 Au-colloid for CNS prophylaxis yielded no pathological CT results. Distinct cortical, subcortical and cerebellar atrophies or calcification of stem ganglia were found in children after one or two CNS irradiations. These CT investigations confirm the results published by other authors, i.e. that owing to an irradiation--cytostatic therapy of the children's brains CNS lesions can be found in the CT. Their prognosis can only be determined by longterm observations. CNS prophylaxis by means of intrathecal 198 Au-colloid and methotrexate does not lead to any pathological CT anomalies.     

Hospital Family Planning: Termination of Pregnancy and Contraceptive Use

A review of termination of pregnancy in a district hospital catchment area for 1970 to 1972 shows how a decrease in total numbers of terminations and repeat terminations may be effected by the use of intensive family planning. In 1972 over 80% had first trimester abortions, but most of the second trimester abortions came from the manual skilled, semi-skilled, and unskilled occupational groups. Over half those attending for termination had never used any method of contraception. Acceptance of family planning after termination was high but motivation poor, emphasizing the suitability of intrauterine devices inserted at the time of termination. The complication rate after termination was low.     

Contribution of ultrasonographic examination to the prenatal detection of chromosomal abnormalities in 19 centres across Europe.

The objective of this study was to evaluate the prenatal detection of chromosomal abnormalities by fetal ultrasonographic examination in a large database provided by 19 Registries of Congenital Anomalies from 11 European countries. This study included 1738 cases of chromosomal abnormalities, liveborn, stillborn or termination of pregnancy regardless of maternal age from a population of 664,340 births during the period 1996 - 1998. The most frequent chromosomal anomalies were Down syndrome (n=1050), trisomy 18 (n=191), Turner syndrome (n=125), trisomy 13 (n=86), and triploidy (n=56). Fetal ultrasonographic examination resulted in the prenatal detection of 37.7% of the chromosomal abnormalities, thereby resulting in a reduction of 28.6% in their prevalence at birth due to terminations of pregnancy. The detection rate by ultrasound examination varied according to local policies of prenatal diagnosis : it was lower in countries where routine scan were not performed and higher in countries in which at least one routine anomaly scan during the second trimester of pregnancy was performed. The ultrasound detection varied according to the specific chromosomal anomaly and was lowest for Klinefelter syndrome (5.7%) and highest for triploidy (78.6%). For Down syndrome it was 26.4%. Termination of pregnancy was performed in 75.9% of the cases. Among the 655 cases detected by ultrasound, the most frequent ultrasound signs by category of chromosomal abnormalities were analysed. This study shows that ultrasound screening is an important tool in the prenatal detection of chromosomal abnormalities in Europe, leading to a significant reduction in the prevalence of livebirth children with chromosomal anomalies.     

Can folic acid protect against congenital heart defects in down syndrome?

BACKGROUND: Several studies have suggested a protective effect of folic acid (FA) on congenital heart anomalies. Down syndrome (DS) infants are known to have a high frequency of heart anomalies. Not all children with DS suffer from heart anomalies, which raises the question whether maternal factors might affect the risk of these anomalies. Our objectives were to investigate whether first-trimester FA use protects against heart anomalies among DS children. METHODS: Women with liveborn DS children participating in the Slone Epidemiology Center Birth Defects Study between 1976 and 1997 were included. We performed case-control analyses using DS, with heart anomalies as cases and DS, without heart anomalies as controls. Subanalyses were performed for defects that have been associated with FA in non-DS populations (conotruncal, ventricular septal [VSD]) and for those that are associated with DS (ostium secundum type atrial septal defects [ASD] and endocardial cushion defects [ECD]). Exposure was defined as the use of any FA-containing product for an average of at least 4 days per week during the first 12 weeks of pregnancy, whereas no exposure was defined as no use of FA in these 12 weeks. RESULTS: Of the 223 cases, 110 (49%) were exposed versus 84 (46%) of the 184 controls. After adjustment for possible confounders, no protective effect of FA was found on heart anomalies overall (OR 0.95, 95% CI: 0.61-1.47) nor separately for conotruncal defects, VSDs, ASDs, or ECDs. CONCLUSIONS: Our study does not show a protective effect of FA on heart anomalies among infants with DS.     

Combined chemotherapy and teratogenicity

BACKGROUND: The concomitant occurrence of breast cancer and pregnancy is relatively uncommon. We report the case of a patient with syndactyly, cleft hands, and absence of distal finger phalanges associated with maternal exposure to chemotherapeutic agents during the first trimester of pregnancy. These associations have not been previously described. CASE: The patient was born by normal delivery after 38 weeks of pregnancy. His mother became pregnant while receiving chemotherapy (cyclophosphamide, 5-fluorouracil, and adriamycin) for breast cancer, and the fetus was exposed to these drugs from conception to the 16th week of pregnancy. At birth, anomalies were observed, including a high-arched palate, microcephaly, a flat nasal bridge, bilateral syndactyly in the first and second fingers with a hand cleft between the second and third fingers and hypoplasia of the fifth fingers, and dystrophic nail of the fourth finger of the left hand. The patient's growth and development were deficient. CONCLUSIONS: The malformations associated with in utero exposure to these chemotherapeutic agents are highly variable, but growth deficiency and anomalies of the craniofacial region and limbs are the most common. The pattern of malformations in children who were congenitally exposed to chemotherapeutic agents appears to be directly related to the age at and duration of exposure, rather than to the specific drug itself. Effective contraception is essential for the safe use of a potential teratogen in nonpregnant women of reproductive age.     

Third trimester abortion for fetal abnormality

Developments in medical technology have increased the possibility of diagnosing severe structural abnormalties in the fetus. If these occur, a woman may request termination of her pregnancy. This raises serious ethical and legal questions, in particular if the anomalies are discovered in the third trimester when the fetus is considered viable. Should doctors be allowed to act upon a request for abortion in such a situation, and, if so, which safeguards should be in place? These questions are discussed with special reference to the Netherlands where a commission established by the government recently published a report on this matter.